A unique finding of normal aldosterone level in Bartter ’ s syndrome

Background: Bartter’s syndrome is a rare autosomal recessive renal tubular disorder characterized by hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronemia with normotension. Bartter syndrome has five types; type 1 (mutation in sodium/potassium chloride transporter), type 2 (mutation in voltage gated potassium channel), type 3 (mutation on chromosome 1 that encodes Barttin and makes only kidney-specific chloride channel B non-functional), type 4 ( mutation in BSND gene encoding Barttin and makes both kidney-specific chloride channels A & B non-functional) and type 5 (L125P gain in function mutation in calcium-sensing receptor). Case Presentation: A 28-year-old male was hospitalized for evaluation of nausea, vomiting, generalized weakness and persistent chronic hypokalemia. Bartter’s syndrome was suspected based on clinical and laboratory evidence, however serum aldosterone level was normal. Further genetic testing confirmed the diagnosis of Bartter’s syndrome type 3. Conclusions: We report a case of Bartter’s syndrome type 3 with a unique finding of normal aldosterone level.


Introduction
Bartter's syndrome is a rare renal tubular disorder that is autosomal recessive in nature (1).The incidence of Bartter's syndrome is 1.2 per million people (2).Bartter et al first described this disease in 1962 and characterized by salt wasting, hypochloremia, hypokalemia, metabolic alkalosis, and frequently associated with recurrent dehydration and failure to thrive (3,4).Besides fluid and electrolyte abnormality, hyperreninemia and hyperaldosteronemia with normal blood pressures are seen in patients with Bartter's syndrome (5,6).The underlying pathology is mutation of genes encoding transport proteins in the thick ascending loop of Henle that decreases reabsorption of sodium in conjunction with increased secretion of potassium and hydrogen in to the urine, resulting in electrolyte and hormonal imbalance (7).We report a case of Bartter's syndrome with an unusual finding of a normal aldosterone level and absence of metabolic alkalosis.

Case Presentation
A 28-year-old Caucasian male presented to emergency room with history of generalized weakness, nausea and vomiting.Also, history of craving for salt, poor appetite and nocturia noted in the past.He was diagnosed to have distal renal tubular acidosis (distal He was started on spironolactone 100 mg oral twice a day along with amiloride to prevent renal potassium loss.In addition, he was also given indomethacin 50 RTA or type 1 RTA) previously and was on bicarbonate therapy.His past medical history is significant for chronic kidney disease (CKD) stage I, chronic hypokalemia and right bundle branch block since the age of 2 years apart from history of hypophosphatemia, hypomagnesemia, pneumothorax and depression.There was a history of multiple hospitalizations for hypokalemia (lowest noted was 0.9 mEq/L) and recurrent abdominal pain, and was on potassium supplementation.His serum electrolytes and renal functions from the last two years are tabulated below in Table 1, and electrolyte trends over time is depicted in Figure 1.He was not evaluated by a nephrologist in the past and family history was significant for hypokalemia (sister).He smokes cigarettes and marijuana.On physical examination, he was a tall, thin and frail person with a body mass index (BMI) of 15.65 kg/ m 2 .His blood pressure was 100/60 mm Hg and abdominal examination was benign.Initial lab work up in the emergency room showed potassium 1.8 mEq/L (normal 3.5-5 mEq/L), spot urine potassium to creatinine ratio >1.5 mEq/mmol creatinine (indicates renal potassium wasting) and bicarbonate was 23 mEq/L (normal 22-28 mE/L).There was no evidence of metabolic alkalosis in the setting of continuous vomiting.He was given intravenous potassium chloride infusion and 0.9% normal saline.We suspected Bartter's syndrome clinically and further evaluation revealed high renin but normal aldosterone level.A 24-hour urine electrolytes showed sodium and potassium wasting, hypermagnesuria and hypercalciuria.A trans-tubular potassium gradient (TTKG) was high indicating renal potassium loss.A substantially lower value (<3) reflects an attempt to conserve potassium in patients with hypokalemia secondary to extra renal losses or an intracellular shift due to diuretic abuse.Genetic testing was consistent with Bartter's syndrome type 3.  Bartter's syndrome with normal aldosterone 361 mg oral once daily to inhibit prostaglandin synthesis and continued oral potassium 40 mEq every 6 hours.His condition improved remarkably and serum potassium normalized.He was discharged home with a plan for intravenous potassium twice a week at an infusion clinic and replenishing phosphate, and was advised to follow up in 2 months.

Discussion
Bartter's syndrome type 1 is caused by frame shift, nonsense and missense mutation in NKCC2 gene (sodium-potassium-chloride co-transporter gene) on chromosome 15 that encodes Na-K-2Cl cotransporter in the thick ascending loop of Henle (8) (Figure 2).Bartter's syndrome type 2 is due to a mutation in ROMK gene (renal outer medullary potassium channel gene) that encodes ATP sensitive potassium channels disrupting the regulation of potassium in the tubular lumen (9).Bartter syndrome type 3 is a salt losing tubulopathy due to a mutation on chromosome 1 that encodes for Barttin and renders only kidney-specific chloride channel B (ClCKB) non-functional (10).Barttin is located in the ascending loop of Henle and the marginal cells of the inner ear, and regulates the chloride channels ClCKA and ClCKB.The current treatment for Bartter's syndrome involves long term potassium replacement, intravenous hydration and prostaglandin synthase inhibitors like indomethacin and ketoprofen (16).Due to the adverse effects of long term medication use, Cox-2 inhibitors like rofecoxib can be substituted (15,17).Rofecoxib can also be administered in patients, refractory to indomethacin treatment (18).A study by Mendonça et al described the use of aliskiren, a direct renin inhibitor, to counteract hyperreninemia in Bartter's syndrome there by reducing the amount of potassium required to be administered therapeutically (19).ACE inhibitors like enalapril have also been described to improve the potassium regulation in Bartter's syndrome (20).

Conclusions
Bartter's syndrome with normal aldosterone level is a rare finding and there is scant amount of literature describing this unique association.To the best of our knowledge there has been no such adult case reported.The approach to such patients needs to be further explored.

Table 1 .
Blood laboratory results